Abstract IA018: Epigenome targeting in ovarian cancer: preclinical models to clinic

Abstract DNA methylation causes silencing of tumor suppressor (TSGs) and differentiation-associated genes, being linked to chemoresistance. Ovarian cancer (OC) is uniquely suited for epigenome targeting as a disease driven by loss of TSGs, rather than oncogenes. Hypomethylating agents (HMA) have been shown to re-sensitize OC to chemotherapy and immunotherapy. A novel HMA (4-thio-decitabine) effectively depleted DNMTs, induced global hypomethylation and transcriptional reprogramming leading to inhibition of OC cell proliferation and tumor growth. Mechanistically, among other gene sets, NTX-301 significantly altered the fatty acid metabolism pathway. A key enzyme in this pathway, the stearoyl co-A desaturase which regulates the last step in lipogenesis, converting saturated fatty acids into unsaturated fatty acids (UFAs) was potently inhibited by NTX-301. This led to depletion of UFAs in cells and tumors treated with the HMA and cell death through ferroptosis. In a clinical trial for women with recurrent, platinum resistant OC, epigenetic priming was used to enhance response to immune checkpoint inhibitors. Among 35 evaluable patients, the clinical benefit rate was 31. 4% (95% CI: 16. 9 – 49. 3%). Methylomic and transcriptomic analyses revealed activation of pathways related to anti-tumor immunity in post-treatment biopsies. High dimensional immune profiling of PBMCs showed higher frequency of peripheral naive and/or central memory CD4+ T cells subsets and of classical monocytes in patients deriving clinical benefit. Multiplex immunohistochemistry indicated that baseline higher density of CD8+ T cells and CD20+ B cells in tumor tissue and presence of putative tertiary lymphoid structures were associated with clinical benefit. These results propose novel mechanisms by which HMAs exert anti-tumor activity in preclinical and clinical models. Citation Format: Daniela Matei. Epigenome targeting in ovarian cancer: preclinical models to clinic abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr IA018.